Review 10.1586/14737140.6.11.1593 © 2006 Future Drugs Ltd ISSN 1473-7140 1593 www.future-drugs.com Recurrent glioblastoma multiforme: advances in treatment and promising drug candidates Lijo Simpson and Evanthia Galanis † † Author for correspondence Mayo Clinic, Department of Oncology, 200 1st Street SW, Rochester, MN 55905, USA Tel.: +1 507 284 2511 Fax: +1 507 284 1803 galanis.evanthia@mayo.edu KEYWORDS: chemotherapy, gene therapy, glioblastoma multiforme, immunotherapy, recurrence, small molecule cell cycle inhibitors Recurrent glioblastoma multiforme is a lethal disease with currently available treatment options having a limited impact on outcome. In this article, current and novel therapeutic approaches in the treatment of recurrent glioblastoma multiforme, including chemotherapy, targeted molecular agents, virotherapy/gene therapy and immunotherapy and challenges in developing novel therapeutic agents for glioblastoma multiforme will be discussed. Expert Rev. Anticancer Ther. 6(11), 1593–1607 (2006) Malignant gliomas are the most common pri- mary brain tumors in adults and account for 18,000 cases each year and 16,000 deaths [1]. Glioblastoma multiforme (GBM), or grade 4 fibrillary astrocytoma, represents the most common glioma histology and has a dismal prognosis despite the use of multimodality treatment (which includes surgery, radiation and chemotherapy), with a median survival of 12–15 months [2]. Until recently, surgery fol- lowed by radiation therapy, with or without the addition of nitrosourea-based chemother- apy, represented the standard of care for newly diagnosed GBM. The recent results of a joint European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute (NCI) of Canada Phase III trial established that concurrent daily temo- zolomide in combination with radiation ther- apy followed by 6 months of adjuvant temo- zolomide should be the new standard of care in patients with newly diagnosed GBM [2]. T his treatment resulted in an increase in median survival of 2.5 months (from 12.1 to 14.6 months) and an absolute increase in 2-year survival of 10%, without a negative impact on the patients’ quality of life [3]. When patients with GBM develop recurrence of the disease, most available treatment options have a limited impact on overall outcome. The 6-month progression-free survival (PFS) ranges from 8 to 15%, median PFS from 8 to 9 weeks and overall survival (OS) from 3 to 4 months [4,5]. In this article, we will review available medical treatment options for recur- rent GBM patients, with a special emphasis on novel treatment directions. Chemotherapy Temozolomide is an oral methylating agent with excellent blood–brain barrier penetration. It currently represents the standard-of-care chemotherapy agent in the treatment of newly diagnosed GBM. Nevertheless, the activity of temozolomide for recurrent GBM is modest. In a randomized Phase II trial comparing temo- zolomide (150–200 mg/m 2 /day for 5 out of 28 days) with procarbazine (150 mg/m 2 /day for 28 out of 56 days) in recurrent GBM patients, temozolomide treatment resulted in an objective response rate of only 5.4%. Nev- ertheless, there was a significant increase in 6-month PFS with temozolomide (21 vs 8%), median PFS (12.4 vs 9.3 weeks) and median OS at 6 months (60 versus 44%) [6]. However, it should be noted that patients in this trial were temozolomide naive and these results cannot necessarily be extrapolated to recurrent GBM patients, who have previously failed first-line temozolomide. Temozolomide activity occurs through DNA methylation. T he O 6 position of gua- nine represents the key methylation target [7]. O 6 -methyl guanine DNA methyltransferase CONTENTS Chemotherapy Molecularly targeted therapy EGFR inhibitors PDGFR inhibitors Ras–MAPK pathway inhibitors PI3K–Akt pathway inhibitors Angiogenesis inhibitors VEGFR inhibitors VEGF inhibitors Inhibitors of protein kinase C Histone deacetylase inhibitors Proteasome inhibitors Agents inhibiting invasion Gene therapy/virotherapy Immunotherapy Expert commentary Five-year view Key issues References Affiliations For reprint orders, please contact reprints@future-drugs.com